Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction
Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction
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DOI：
10.1002/psp4.12457
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发表时间：
2019-11-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
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作者：
Asaumi, Ryuta;Menzel, Karsten;Sugiyama, Yuichi
由于利福平可以引起多种代谢酶和转运蛋白的诱导和抑制，因此准确预测复杂的药物-药物相互作用(DDiS)一直是一个具有挑战性的问题。我们先前构建了利福平的生理药代动力学(PBPK)模型，该模型考虑了诱导细胞色素P450(CYP)3A/CYP2C9和抑制有机阴离子转运多肽1B(OATP1B)的成分。本研究旨在通过引入诱导OATP1B和CYP2C8以及抑制多药耐药蛋白2的额外成分来扩展和验证利福平的PBPK模型。所建立的PBPK模型能够准确地预测不同给药方案下复杂利福平诱导的格列本脲、瑞格列奈和共比例卟啉I(OATP1B活性的内源性生物标志物)的变化。我们全面的利福平PBPK模型可以定量预测由多种代谢酶和转运体处理的各种潜在受害者药物和内源性生物标记物的DDIS。
As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug-drug interactions (DDIs). We previously constructed a physiologically-based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin-induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.